Project Summary Alcohol use disorders (AUDs) are a major public health problem in the United States. While the FDA has approved 3 new medications in the past 20 years (oral naltrexone, long-acting intramuscular naltrexone, acamprosate), these agents have small effect sizes in reducing drinking when studied in AUD patients in general and their clinical use is limited. To move the treatment of AUD forward there is a compelling need to find new medications that are both effective and well tolerated. Oxytocin (OT), a neuropeptide with a range of neurobiological actions, has been shown in animal models to counteract alcohol-induced tolerance and reduce drinking. We have conducted pilot clinical trials testing the efficacy of intranasal OT in AUD. Evidence indicates that intranasal administration results in penetration of oxytocin into the CNS in human subjects. Following our initial report that intranasal OT potently blocks withdrawal in highly dependent subjects, we obtained NIAAA R21 funding and conducted a 12-week double blind pilot clinical trial testing intranasal OT in heavy drinking subjects with AUD (22 randomized). Compared to placebo, OT very significantly decreased drinks/drinking day (2.6 fewer drinks/drinking day with OT, p=.0008) and significantly decreased heavy drinking days (~15 fewer heavy drinking days [?5 standard drinks/day in men, ?4 in women] over the trial, p=.047). These pilot studies indicate that OT treatment has potential therapeutic effects in AUD?however these trials are small. Therefore, for the proposed study, Specific Aim 1 is to more rigorously test our hypothesis that intranasal OT is effective in reducing drinking (heavy drinking days, drinks/drinking day) by conducting a larger randomized, placebo-controlled trial in subjects who meet DSM-V criteria for moderate or severe AUD (N=80). Half of the cohort will meet the criteria for heavy drinking that were required for participation in our above mentioned positive pilot study (?35 drinks/week in men, ?28 in women for 4 weeks prior to study entry) and half will include subjects who drink less so the results of the study will be more widely relevant to the U.S. AUD population. Randomization will factor in gender and heavy drinking status. Overall, the proposed trial is an exciting translational study that builds upon positive basic science results and significant preliminary clinical trial findings. The identification of novel molecular agents such as OT that may truly reduce drinking in patients with AUD is a critical goal of clinical research and one that could significantly advance the treatment of the millions of individuals who suffer from AUD.